CN113149886A - Synthesis method of silodosin - Google Patents

Synthesis method of silodosin Download PDF

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CN113149886A
CN113149886A CN202110342979.0A CN202110342979A CN113149886A CN 113149886 A CN113149886 A CN 113149886A CN 202110342979 A CN202110342979 A CN 202110342979A CN 113149886 A CN113149886 A CN 113149886A
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silodosin
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CN113149886B (en
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任峰波
徐国轩
戴学仁
王岩
马鑫
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Hangzhou Ledun Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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Abstract

The invention discloses a synthesis method of silodosin, which takes indoline as a raw material and sequentially carries out amino protection, bromination and deprotection; then passing through SN2Reacting to obtain a compound 3; d-alanine and benzyl chloroformate are subjected to substitution reaction and Mannich reaction to obtain a chiral compound 6; then the compound 3 and the chiral compound 6 are connected together by a Grignard reagent; then reducing carbon group with triethylsilane and TFA to obtain a compound 8; then substituting and deprotecting a group Cbz to obtain a compound 9; SN Generation from Compounds 9 and 122Substitution reaction to obtain a compound 10; finally, hydrogenation/Pd/C deprotection is carried out, and hydrogen peroxide oxidizes cyano to form amide, so as to obtain the product silodosin. The compound 3 and the chiral compound 6 are synthesized to obtain the key chiral compound 7, so that the resolution is avoided, the optical purity is controllable, the reaction yield is improved, the reaction condition is mild, a large amount of byproducts obtained in the resolution of the old process are avoided, the production cost is reduced, the purity is high, the method is environment-friendly, and the industrial production is easy to realize.

Description

Synthesis method of silodosin
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of silodosin for treating prostatic hyperplasia.
Background
Cilostaxin (silodosin) is a selective α 1A-adrenergic blocker, and preclinical studies have shown that it has 12 and 7.5 times higher selective effects on the urethra than Prazosin (Prazosin) and Tamsulosin (Tamsulosin), respectively. Silodosin can obviously inhibit the contraction of human prostate caused by norepinephrine; has dose-dependent inhibition effect on hyperactivation of bladder in a rat benign prostatic hyperplasia model, and can improve the pressure threshold of bladder contraction. These data suggest that silodosin is effective in alleviating symptoms associated with benign prostatic hypertrophy in addition to improving bladder function.
Benign Prostatic Hyperplasia (BPHI) is one of the common diseases in elderly men and is characterized by non-malignant enlargement of the prostate. More than 50% of elderly people aged 60 years or older suffer from this disease, while more than 90% of elderly people aged 85 years and older suffer from the disease. The cause of the disease has not been elucidated, but it is thought to be related to the secretion and metabolism disorder of sex hormones, cholesterol and the like. It is believed that the aged deteriorates the function of pituitary-gonadotropin-testis or has endogenous changes, which causes degeneration of testis, decreased sexual function, decreased testosterone level, increased connective tissue of prostate, change of glandular epithelium, and enlargement of prostate. The enlargement of the prostate gland can press against the urethra, resulting in a poor urinary flow from the bladder and even blockage of the bladder outlet. In the human prostate, there is a 1A-adrenoceptor, activation of which exacerbates the symptoms of aureola and dysuria in the urethra. Therefore, by blocking the binding of a 1A-adrenoceptor, the obstructed prostate smooth muscle can be relaxed, thus ameliorating the symptoms.
A study of the dosing of benign prostatic hyperplasia patients in 2009 showed that: the consumption of the daily medication of 70% of patients is 6.52-27.3 yuan, between 2010 and 2012, and the medicine market is increased by 30% every year. The market value of prostate drugs in China is estimated to be more than 20 million yuan. Tamsulosin, a congeneric drug of silodosin, has achieved great clinical success, and currently, the market share of tamsulosin in benign prostatic hyperplasia is ranked the second place, which is about 15%. And cilostacin has a stronger effect than tamsulosin, and thus it is expected that it will have remarkable market performance.
Benign prostatic hyperplasia is one of the most common diseases of male middle-aged and elderly people, and urination obstruction symptoms and irritation symptoms caused by the benign prostatic hyperplasia bring great influence on the life of the elderly people. Epidemiological survey data of benign prostatic hyperplasia in European and American areas show that the incidence rate is quite high, and the age groups of the benign prostatic hyperplasia are 8-49 years old, 20-50-59 years old, 35-60-69 years old and 43-70 years old.
The incidence of benign hyperplasia of prostate in Chinese was low in 2000 years ago. However, in recent years, with the increasing level of industrialization in China, the intake of animal protein is gradually increased, the life is prolonged, and the incidence of benign prostatic hyperplasia is increased year by year. According to statistics of research institute of urology of Beijing medical university, incidence rates of benign prostatic hyperplasia in years 2007-2010 are 13.2% in age 41-50, 20% in age 51-60, 50% in age 61-70, 57.1% in age 71-80 and 83.3% in age 81-90. While epidemiological investigations carried out in the Shanghai have shown that the rate of benign prostatic hyperplasia in male residents over 40 years old is 43% (680/1582). It is seen that the incidence of benign prostatic hyperplasia in the large cities of China is close to the level of benign prostatic hyperplasia in the developed countries of the west. Of the patients with prostatic hyperplasia, 25% require medication or surgical treatment. Prostatic hyperplasia can cause obstruction of the bladder neck, and urination symptoms of different degrees produced by the obstruction can bring great influence on the life of the old.
Prostate removal surgery has long been the only treatment, with good results and low mortality rates, but still causes different degrees of patient injury. Therefore, the search for an effective, safe and non-operative treatment method which can prevent the development of diseases and relieve the symptoms of the patients is a commonly-sought target for a long time. In recent years, the clinical use of 5 a-reductase inhibitors and a 1-adrenoceptor ((alpha 1-AR) blockers, respectively, has achieved good results, and is considered to be a major achievement of drug therapy for prostate hyperplasia.
Currently used clinically, finasteride (Finasterida) is a 5 a-reductase II inhibitor that inhibits DHT levels in plasma and prostate tissues without affecting testosterone. Generally, the maximum curative effect appears half a year after administration. The a 1-AR blockers are effective in relaxing bladder neck and prostate smooth muscle, thereby rapidly relieving the obstructive symptoms of prostatic hyperplasia without reducing the enlarged prostate volume. In view of the high incidence rate of benign prostatic hyperplasia in elderly male patients and the few clinical available drugs, the development of a drug for treating benign prostatic hyperplasia has good social benefit and good economic benefit.
Silodosin (Silodosin) is an a 1A-receptor antagonist developed by Kissei pharmaceutical company, japan, has a selective inhibitory effect on urethral smooth muscle contraction and reduces intraurethral pressure without greatly affecting blood pressure, and is clinically used for treating dysuria due to benign prostatic hyperplasia. At present, a plurality of reports about the synthesis method of silodosin exist, but the defects mainly lie in low yield and are not suitable for industrial production.
Japanese patent application JP200199956 discloses a synthetic route for the compound.
Figure BDA0003000073320000031
The synthetic route takes benzoic acid as a raw material to prepare 1- (3-benzoyloxypropyl) indoline hydrochloride with the yield of 60.09%; then preparing a compound 3 from aldehyde group on 5-position of indoline, reacting with nitroethane to synthesize a nitropropene compound 4, wherein the yield of the two steps is 69.83%, and then reducing olefinic bond with sodium borohydride to prepare a compound 5, and the yield is 99.65%; then preparing a compound 6 by aldehyde group on 7-position of indoline, wherein the yield is 80.6%; then reacting with hydroxylamine hydrochloride and dehydrating with acetic anhydride to obtain a 7-cyano compound 7 with the yield of 62.56 percent; finally, the product reacts with potassium carbonate and 30 percent hydrogen peroxide and is refined by a chromatographic column. The compound 8 and L- (S) -phenylglycine undergo asymmetric reaction under the catalysis of platinum oxide, and the chiral induction rate is low and is 3.8:1 probably because the steric hindrance of a protecting group is small.
The biggest defects of the route are that the yield is too low, only 30 percent is not obtained, the impurity is more, the content is not high, generally about 87 percent, and the quality requirement is difficult to achieve. And the intermediate reaction has more waste water, complex components and great treatment difficulty. Therefore, the production cost is high, the environmental pollution is high, and large-scale social production is difficult to carry out. Among other disadvantages is that the appearance is unacceptable and the finished product is always brown. The synthesis steps are multiple, the purification is carried out by a chromatographic column, a large amount of dichloromethane and methanol are needed, and the boiling point of dichloromethane is lower, so that the yield in the recovery process is low, the environmental protection pressure is increased, the production cost is increased, and the industrial production is not suitable.
The synthetic route disclosed in chinese patent publication No. CN101993407A is:
Figure BDA0003000073320000041
the synthetic route is to take 1- (3-substituted benzoyl acyloxy propyl) element) -5- (2-nitro propyl) -7-cyano indoline as raw materials in DBU, triethyl chlorosilane and H2O2Then, nitro is oxidized into carbonyl, then R- (+) -alpha-phenylethylamine is split to obtain a chiral intermediate, palladium carbon is hydrogenated and then salified with L-tartaric acid, and then the subsequent reaction step is carried out, wherein the splitting is required in the reaction process.
The disadvantages of the route are that in the process of synthesizing the intermediate, in order to obtain a household product with R configuration, a large amount of methanol is used in the process of splitting R- (+) -alpha-phenylethylamine, the yield of the product is very low and is not more than 20%, the purity of the product is not high, multiple refining is needed to obtain a qualified product, the yield is very low, expensive platinum oxide and palladium carbon are used in the subsequent synthesis process, the recovery and the utilization are troublesome, and the defects cause great reaction operation difficulty and high cost, and are not beneficial to industrial production.
Japanese invention patent JP200226544 discloses a synthetic route for a compound:
Figure BDA0003000073320000051
the synthetic route obtains the target compound 5- [ (2R) -2-aminopropyl ] -1- [3- (benzoyloxy) ] -7-cyanoindoline by resolving the compound 11.
The disadvantages of this route: the method has long synthesis route and low resolution yield, and the used resolution reagent is not easy to obtain and is not suitable for large-scale production.
The chinese patent application with publication number CN101759627 uses 1-acetyl indoline as raw material to obtain racemic intermediate through multi-step reaction, and also performs subsequent reaction steps after chiral resolution of mandelic acid. And in the reaction process, a reaction reagent 2-bromopropionyl chloride, NBS is needed, and trifluoroacetic acid is used twice.
The disadvantages of this route: the 2-bromopropionyl chloride used in the synthesis process is difficult to obtain, a single monobromo product cannot be obtained by carrying out a free radical reaction on N-bromosuccinimide, reaction byproducts are more, trifluoroacetic acid has serious corrosion to equipment, great harm to the environment and high environmental protection pressure, and is not beneficial to green production, and the defects cause great reaction operation difficulty and industrial production.
Disclosure of Invention
The invention aims to solve the technical problems that when silodosin is prepared in the prior art, a column chromatography and other working procedures are needed due to a complex preparation process, chiral separation is needed in an intermediate synthesis process, so that the reaction operation difficulty is high, the yield is low, the industrial production is not facilitated and the like, and provides a novel silodosin synthesis method.
The technical problem to be solved by the invention is realized by the following technical scheme:
a method for synthesizing silodosin comprises the following steps:
(1) sequentially carrying out amino protection, bromination and deprotection reactions on indoline to obtain 5-bromoindoline 2;
Figure BDA0003000073320000061
(2) 5-bromoindoline 2 and 2- (3-chloro)Propoxy) tetrahydro-2H-pyran to SN2Reacting to obtain 5-bromo-1- [ 2-tetrahydropyran]Ethyl } -2H indole;
Figure BDA0003000073320000062
(3) performing substitution reaction on D-alanine and benzyl chloroformate to obtain an intermediate, performing Mannich reaction on the intermediate and formaldehyde to form a ring to obtain a cyclic ester compound;
Figure BDA0003000073320000063
(4) reacting the cyclic ester compound obtained in the step (3) with a Grignard reagent, reacting the obtained intermediate with the 5-bromo-1- [ 2-tetrahydropyran ] ethyl } -2H indole obtained in the step (2) to obtain a compound 7, and sequentially carrying out reduction, benzoyl substitution and bromination on the compound 7 to obtain a compound 8;
Figure BDA0003000073320000064
(5) carrying out substitution reaction on the compound 8 and cuprous cyanide, and then removing a protecting group-CbZ to obtain a compound 9;
Figure BDA0003000073320000071
(6) compound 9 and 2- [2- (2,2, 2-trifluoroethoxy) phenoxy]Ethyl methanesulfonate 12 to SN2Substitution reaction to obtain a compound 10;
Figure BDA0003000073320000072
(7) removing a protecting group BZ from the compound 10, and oxidizing to obtain the silodosin;
Figure BDA0003000073320000073
according to the preparation method, indoline is used as a raw material and reacts with acyl chloride to generate an amide intermediate 1 for protecting amino, then bromine is added to an indole ring to obtain an intermediate 2, and acetyl is removed to obtain a compound 2; then with
Figure BDA0003000073320000074
Generating SN2Reacting to obtain a compound 3; d-alanine and benzyl chloroformate are subjected to substitution reaction and Mannich reaction to obtain a chiral cyclization compound 6; then the compound 3 and the compound 6 are connected together by a Grignard reagent to obtain a key chiral intermediate 7; then reducing carbonyl by triethylsilane and TFA to obtain a compound 8; then substituting and deprotecting a group Cbz; then 2- [2- (2,2, 2-trifluoroethoxy) phenoxy]Methanesulfonic acid reaction SN of Ethyl methanesulfonate2Substitution reaction to obtain a compound 10; finally, classical hydrogenation/Pd/C deprotection is carried out, and hydrogen peroxide oxidizes cyano to form amide to obtain the compound 11 silodosin.
Figure BDA0003000073320000075
Figure BDA0003000073320000081
Preferably, in the step (1), acetyl chloride is used as a protective reagent for amino protection;
the brominating reagent is bromine, and the brominating is carried out in acetic acid;
the deprotection reaction is carried out in a mixed solvent of ethanol and water under the action of HCl.
In the step (1), the amino protection, the bromination and the deprotection do not need to be subjected to column chromatography treatment, and are extracted by dichloromethane, the solvent is removed, and then the next step is carried out.
Preferably, in the step (2), the SN is2The reaction is carried out in DMF under the action of inorganic base and potassium iodide.
The inorganic base is preferably sodium carbonate or potassium carbonate.
The 2- (3-chloropropoxy) tetrahydro-2H-pyran is added in a dropwise adding mode, the dropwise adding temperature is 90-100 ℃, and the reaction is carried out at 130 ℃ after the dropwise adding is finished.
In the step (2), after the reaction is finished, water and ethyl acetate are added for extraction, the organic phase is decompressed to remove the solvent, and then the 5-bromo-1- [ 2-tetrahydropyran ] ethyl } -2H indole is obtained by recrystallization with toluene.
Preferably, in the step (3), the substitution reaction is carried out in water under the action of sodium hydroxide;
the Mannich reaction is carried out in toluene under the catalysis of p-toluenesulfonic acid.
After the substitution reaction is finished, the pH value is adjusted to 2 by hydrochloric acid, then toluene is used for extraction, the solvent is removed under reduced pressure, and the Mannich reaction step is directly carried out.
After the Mannich reaction is finished, washing with water is carried out, and the solvent is removed to enter the step (4).
Preferably, in step (4), the Grignard reagent is i-PrMgCl.
In the step (4), the reaction for preparing the compound 7 is carried out at the temperature of-25 to-20 ℃, after the reaction is finished, the reaction is quenched by water, the pH value is adjusted to 7 by dilute hydrochloric acid, then the extraction is carried out by toluene, organic phases are combined, and the next step is directly carried out after the solvent is removed.
Preferably, in step (4), the reduction is carried out under the action of triethylsilane and TFA.
Preferably, in step (5), the substitution reaction is carried out in DMF under the action of sodium iodide.
Preferably, in step (5), the deprotection is carried out under catalytic hydrogenation conditions, and the catalyst used for catalytic hydrogenation is Pd/C.
Preferably, in step (6), the SN is2The substitution reaction is carried out in a tert-butyl alcohol solvent at a temperature of 80-90 ℃.
Preferably, in the step (7), the oxidant used for oxidation is hydrogen peroxide.
Further, the specific scheme is as follows:
1.0 equivalent of indoline in the general formula 1 is used as an initial raw material, 1.1 equivalent of acetyl chloride and amino are firstly used for reacting to form amide, then bromine is reacted by a bromine and acetic acid system, the yield is 96 percent, finally, HCl, ethanol/water are used for processing, and acetamide is deacetylated at 78 ℃ for 4.0h to obtain 2, 5-bromoindoline in the general formula 2, the yield is 98 percent;
the general formula of 25-bromoindoline is 1.1 equivalent of potassium carbonate, 0.5 equivalent of potassium iodide, DMF and 130 ℃
Figure BDA0003000073320000091
Regenerated SN2Reacting for 6h, extracting and concentrating to obtain the general formula 35-bromo-1- [ 2-tetrahydropyran]Ethyl } -2H indole.
Figure BDA0003000073320000092
(2)1.0 equivalent of general formula 4D-alanine and 1.05 equivalent of Cbcl (benzyl chloroformate) substitution reaction, get general formula 5; then the general formula 5 is catalyzed by 1.1 equivalent of p-toluenesulfonic acid in a toluene system and reacts with formaldehyde through Mannich reaction for 12h, and then the cyclic ester of the general formula 6 is obtained through ring formation.
Figure BDA0003000073320000093
(3) The Grignard reagent attacks the carbonyl of the cyclic ester with the general formula 6, nucleophilic addition reaction is firstly carried out, alkoxy leaves to obtain open-ring ketone, the temperature is controlled to be below 20 ℃ below zero, otherwise the open-ring ketone can continue to react with the Grignard reagent; then generating SN with the general formula 32Reacting to obtain a general formula 7; the double bond of the ketone in the general formula 7 is firstly reduced by triethylsilane and TFA, and then-THP is replaced and removed by benzoyl chloride; finally, bromine is added to the indole ring, and the indole ring is quenched, extracted and concentrated to obtain the general formula 8.
Figure BDA0003000073320000101
(4) In the general formula 8, firstly-Br is activated by 0.5 equivalent of NaI and then reacts with 1.1 equivalent of cuprous cyanide at the temperature of DMF130 ℃ to form a cyano-substituted compound after 8.0 h; finally using Pd-C, H2Reducing and removing a protecting group-CbZ, extracting after 6h, and concentrating to obtain the general formula 9.
Figure BDA0003000073320000102
(5) Amino group in the general formula 9 and 1.12 equivalent of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy group at 80-90 ℃ in a tert-butanol system]Methylsulfonyl acid group of ethyl methanesulfonate ester reacts to SN2Substitution reaction, after 6.0h, gave general formula 10 in 67% yield.
Figure BDA0003000073320000103
(6) General formula 10 first Pd-C, H2Under the action, the protecting group Bz (benzoyl) is reduced and removed within 4.0 h; then cyano is oxidized into amide by 1.2 equivalent hydrogen peroxide in a DMSO system to obtain a general formula 11, and the amide is extracted, concentrated, filtered, decompressed and dried, and the yield is 80%.
Figure BDA0003000073320000111
Compared with the prior art, the invention has the beneficial effects that:
(1) the method utilizes the Grignard reagent, the protective group, the Mannich reaction, a series of substitution reactions and catalytic hydrogenation reduction, simplifies the splitting process, improves the yield, has high product purity, reduces the labor intensity and is beneficial to industrial production;
(2) the compound 3 and the chiral compound 6 are synthesized to obtain the key chiral compound 7, so that the resolution is avoided, the optical purity is controllable, the reaction yield is improved, the reaction condition is mild, a large amount of byproducts obtained in the resolution of the prior art are avoided, the production cost is reduced, the purity is high, and the method is environment-friendly and easy for industrial production.
Detailed Description
Example 1 general formula 2 Synthesis
Adding 20g (0.168mol) of indoline of the general formula 1 into a flask, dropwise adding 14.5g (0.185mol) of acetyl chloride at 20 ℃, adding 100g of water for quenching after the reaction is finished, then extracting by using 100g of DCM (dichloromethane), removing the solvent by DCM (DCM) under reduced pressure to obtain an intermediate 1, adding 20ml of acetic acid, and directly using as the next step; 26.8g (0.168mol) Br was added dropwise at 20-25 deg.C2Reacting the mixture with 20ml of acetic acid at 25-30 ℃ for 3 hours, adding 100g of water, adding 100ml of DCM, separating, removing the solvent by the DCM phase under reduced pressure to obtain 38.68g of intermediate 2, wherein Y is 96 percent and is directly used as the next step; 100g of ETOH/water (2:1) was added, 20g of concentrated hydrochloric acid was added, the temperature was raised to 78 ℃ and the reaction was carried out for 4 hours, after the completion of the reaction, the temperature was lowered to room temperature, ethanol was removed under reduced pressure, 50g of DCM was used each time for extraction three times, drying was carried out, and the solvent was removed under reduced pressure to give 31.25g of 5-bromoindoline, Y was 98%, and the HPLC purity was 97%.
1H NMR(500MHz,CDCl3): δ 7.26-7.22(m,2H), 7.15(m,1H), 5.98(s,1H), 3.63-3.56(m,2H), 2.02-1.96(m, 2H). MS: 197-. HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min.
Example 2 general formula 3 Synthesis
A flask was charged with 30g (0.151mol) of the compound 2 (5-bromoindoline), 23g (0.166mol) of potassium carbonate, 12.6g (0.08mol) of potassium iodide, and 90g of DMF, heated to 90 to 100 ℃ and then added dropwise with 29.8g (0.167mol) of 2- (3-chloropropyloxy) tetrahydro-2H-pyran
Figure BDA0003000073320000121
Heating to 130 ℃ for reaction for 6h, after the reaction is finished, adding 200g of water, extracting with 80g of ethyl acetate for three times, removing the solvent by organic phase decompression, and recrystallizing with 110g of toluene to obtain 46.4g of 5-bromo-1- [ 2-tetrahydropyran]Ethyl } -2H indole, Y ═ 90%, HPLC purity 98%.
1H NMR(500MHz,CDCl3): δ 7.22-7.18(m,2H), 7.06(m,1H), 4.60(m,1H), 3.78-3.61(m,6H), 3.35(m,2H),2.96(m,2H),1.81-1.56(m, 8H). MS 339-. HPLC: XDB-C184.6 x 250, acetonitrile/water 1:1，230nm，45min。
example 3 Synthesis of general formula 6
Adding 35g (0.393mol) of D-alanine (compound 4), 33g (0.825mol) of sodium hydroxide and 150g of water into a flask, dropwise adding 1.05 equivalent of 70.4g (0.41mol) of CbzCl (benzyl chloroformate) at 10-15 ℃, raising the temperature to 20-30 ℃ for 5 hours, adjusting the pH to 2 by using 3M hydrochloric acid after the reaction is finished, extracting the solution three times by using 100g of toluene each time, and removing the solvent under reduced pressure to obtain a general formula 5 which is directly used for the next reaction; then, in general formula 5, 180g of toluene, 1.1 equivalent of 74.4g (0.432mol) of p-toluenesulfonic acid and 11.8g (0.393mol) of formaldehyde are added, stirring is started, the reaction is carried out at 20-25 ℃ for 12h, the toluene phase is washed twice with water after the reaction is finished, the toluene phase is collected, and the solvent is removed under reduced pressure to obtain 86.9g of the compound of general formula 6, wherein Y is 94% and the HPLC purity is 97%.
1H NMR(500MHz,CDCl3): δ 7.35-7.28(m,5H), 5.80-5.71(m,2H), 5.02(s,2H), 4.53-4.50(m,1H), 1.51(d, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min.
Example 4 Synthesis of general formula 8
Adding 90g of THF and 50g (0.213mol) of the compound of the general formula 6 into a reaction bottle, cooling to below-20 ℃, dropwise adding 128ml of a THF solution of 1.2eq 2M i-PrMgCl, keeping the temperature between-25 and-20 ℃ after adding, reacting for 2 hours, dropwise adding 72.3g (0.213mol) of compound 3 dissolved in 50ml of THF, keeping the temperature between-25 and-20 ℃ after adding, reacting for 5 to 6 hours, adding 150g of water to quench the reaction, adjusting the pH to 7 by using dilute hydrochloric acid, separating, extracting an aqueous phase by using 100g of toluene, combining organic phases, drying, removing the solvent under reduced pressure to obtain compound 7, and directly using the compound 7 as the next step; adding 200g of TFA into the compound 7, controlling the temperature to be 15-20 ℃, dropwise adding 37.1g (0.318mol) of triethylsilane, heating to 30-35 ℃ after adding, reacting for 8-9 hours, cooling to 0-5 ℃ after reacting, dropwise adding 250g of water to quench, extracting with 100g of toluene for three times each time, collecting a toluene phase, removing the solvent under reduced pressure, and adding 300g of DCM into the residue to directly carry out the next step; at room temperature, 18.5g (0.234mol) of pyridine is added into the solution, the temperature is reduced to 15-20 ℃, 31.4g (0.223mol) of benzoyl chloride is dripped, the mixture reacts for 3-4 hours at room temperature after the addition, 150g of water is added after the reaction, the mixture is separated,extracting water phase with 100g DCM, mixing organic phases, washing the organic phase with small amount of dilute hydrochloric acid and saturated salt water in sequence, drying the organic phase, removing solvent under reduced pressure, and directly carrying out the next step on the residue; adding 100g acetic acid into the residue, cooling to 5-10 deg.C, and adding 15.7g (0.01mol) Br dropwise2After the addition, the temperature is raised to room temperature for reaction for 5-6 hours, after the reaction is finished, 100g of the mixture is added, the water phase is extracted three times by 80g of DCM, the organic phases are combined, the organic phase is washed once by a small amount of saturated sodium carbonate aqueous solution, water and saturated salt sequentially, the organic phase is dried, the solvent is removed under reduced pressure, and 100ml of ethyl acetate and petroleum ether 2 are added into the residue: 1 to yield 27.3g of the compound of formula 8 in a total yield of 23.1%. HPLC purity 98.7%, ee 98.5%.
1H NMR(500MHz,CDCl3): δ 8.09-8.06(m,2H), 7.70-7.56(m,4H), 7.40-7.33(m,5H), 7.09-6.95(m,2H), 5.03(s,2H), 4.32-4.22(m,3H), 3.78-3.60(m,4H), 2.99(m,2H), 2.80-2.71(m,2H),1.99(m, 2H), 1.51(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.
Example 5 Synthesis of formula 8
Adding 100g of THF, 55g (0.234mol) of the compound of the general formula 6 and liquid nitrogen into a reaction bottle, cooling to below-70 ℃, dropwise adding 128ml of 1.2eq 2.2M n-hexane solution of butyllithium (n-BuLi), keeping the temperature between-70 ℃ and-60 ℃ after adding, reacting for 3 hours, dropwise adding 79.5g (0.234mol) of the compound 3 dissolved by 55ml of THF, keeping the temperature between-35 ℃ and-30 ℃ after adding, reacting for 5-6 hours, adding 160g of water to quench the reaction, adjusting the pH to 7 by using dilute hydrochloric acid, separating, extracting an aqueous phase by using 110g of toluene, combining organic phases, drying, removing the solvent under reduced pressure to obtain the compound 7, and directly using the compound 7 as the next step; adding 220g TFA into the compound 7, controlling the temperature at 15-20 ℃, dropwise adding 40.8g (0.35mol) triethylsilane, heating to 30-35 ℃ after adding, reacting for 8-9 hours, cooling to 0-5 ℃ after reacting, dropwise adding 275g water, quenching, extracting with 110g toluene for three times each time, collecting a toluene phase, removing the solvent under reduced pressure, and adding 330g DCM into the residue to directly carry out the next step; at room temperature, upwardsCooling 20.4g (0.26mol) of pyridine in the solution to 15-20 ℃, dropwise adding 34.5g (0.256mol) of benzoyl chloride, reacting at room temperature for 3-4 hours after the addition is finished, adding 160g of water after the reaction is finished, separating liquid, extracting an aqueous phase by 110g of DCM, combining organic phases, washing the organic phase by a small amount of dilute hydrochloric acid and saturated salt water in sequence, drying the organic phase, removing the solvent under reduced pressure, and directly carrying out the next step on the residue; adding 110g acetic acid into the residue, cooling to 5-10 deg.C, and adding 17.3g (0.01mol) Br dropwise2After the addition, the temperature is raised to room temperature for reaction for 5 to 6 hours, after the reaction is finished, 110g of the mixture is added, the water phase is extracted for three times by 90g of DCM, the organic phases are combined, the organic phase is washed once by a small amount of saturated sodium carbonate aqueous solution, water and saturated salt solution, the organic phase is dried, the solvent is removed under reduced pressure, and the residue is added with 110ml of ethyl acetate and petroleum ether 2:1 to yield 17.8g of the compound of formula 8 in a total yield of 13.7%. HPLC purity 98.5%, ee 98.3%.
1H NMR(500MHz,CDCl3): δ 8.09-8.06(m,2H), 7.70-7.56(m,4H), 7.40-7.33(m,5H), 7.09-6.95(m,2H), 5.03(s,2H), 4.32-4.22(m,3H), 3.78-3.60(m,4H), 2.99(m,2H), 2.80-2.71(m,2H),1.99(m, 2H), 1.51(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.
Example 6 Synthesis of general formula 8
Adding 110g of THF, 60g (0.26mol) of the compound of the general formula 6 and liquid nitrogen into a reaction bottle, cooling to below-78 ℃, dropwise adding 155ml of a THF solution of 1.2eq 2M LDA (lithium diisopropylamide), keeping the temperature between-78 ℃ and-70 ℃ after adding, reacting for 1.5 hours, dropwise adding 86.7g (0.26mol) of compound 3 dissolved in 60ml of THF, keeping the temperature between-50 ℃ and-45 ℃ after adding, reacting for 3-4 hours, adding 180g of water to quench the reaction, adjusting the pH to 7 by using dilute hydrochloric acid, separating, extracting an aqueous phase by using 120g of toluene, combining organic phases, drying, removing the solvent under reduced pressure to obtain compound 7, and directly using the compound 7 as the next step; adding 240g TFA into the compound 7, controlling the temperature at 15-20 ℃, dropwise adding 44.5g (0.38mol) triethylsilane, heating to 30-35 ℃ after adding, reacting for 8-9 hours, cooling to 0-5 ℃ after reacting,dropwise adding 300g of water to quench and react, extracting with 120g of toluene for three times each time, collecting a toluene phase, removing the solvent under reduced pressure, and adding 360g of DCM into the residue to directly carry out the next step; at room temperature, 22.2g (0.28mol) of pyridine is added into the solution, the temperature is reduced to 15-20 ℃, 37.7g (0.28mol) of benzoyl chloride is dripped, the mixture reacts for 3-4 hours at room temperature after the addition, 180g of water is added after the reaction, liquid separation is carried out, the water phase is extracted by 120g of DCM, the organic phases are combined, the organic phases are washed once by a small amount of dilute hydrochloric acid and saturated salt in sequence, the organic phases are dried, the solvent is removed under reduced pressure, and the residue is directly carried out in the next step; adding 120g acetic acid into the residue, cooling to 5-10 deg.C, and adding 18.8g (0.012mol) Br dropwise2After the addition, the temperature is raised to room temperature for reaction for 5 to 6 hours, after the reaction is finished, 120g of the mixture is added, the water phase is extracted three times by 100g of DCM, the organic phases are combined, the organic phase is washed once by a small amount of saturated sodium carbonate aqueous solution, water and saturated salt solution, the organic phase is dried, the solvent is removed under reduced pressure, and the residue is added with 120ml of ethyl acetate and petroleum ether 2:1 to give 16.9g of the compound of the formula 8 in a total yield of 11.9%. HPLC purity 98.4%, ee 98.4%.
1H NMR(500MHz,CDCl3): δ 8.09-8.06(m,2H), 7.70-7.56(m,4H), 7.40-7.33(m,5H), 7.09-6.95(m,2H), 5.03(s,2H), 4.32-4.22(m,3H), 3.78-3.60(m,4H), 2.99(m,2H), 2.80-2.71(m,2H),1.99(m, 2H), 1.51(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.
Example 7 Synthesis of general formula 9
Adding 50g (0.09mol) of the compound with the general formula 8, 0.5 equivalent of 6.8g (0.045mol) NaI, 1.1 equivalent of 8.9g (0.1mol) cuprous cyanide and 250g of DMF into a reaction bottle, heating to 130 ℃, reacting for 8-9 hours, removing the solvent DMF under reduced pressure after the reaction is finished, adding 150g of water, extracting with 100g of DCM for three times, drying the organic phase, removing the solvent under reduced pressure, and directly carrying out the next step on the residue; to the residue were added 150g of ethanol and 5g of 5% Pd/C, and the mixture was put into a pressure autoclave, nitrogen was substituted three times, hydrogen was substituted two times, hydrogen was introduced to 0.3 to 0.35MPa, the temperature was raised to 35 to 40 ℃ to react for 4 to 5 hours, after the reaction was completed, the catalyst was recovered by suction filtration, 7g of diatomaceous earth was added and stirred for 30 minutes, and the diatomaceous earth was removed by filtration to obtain 23g of compound 9, wherein Y was 70%, HPLC purity was 98%, and ee value was 98.7%.
1H NMR(500MHz,CDCl3): δ 8.09-8.06(m,2H),7.68-7.56(m,3H), 7.42-7.25(m,2H), 4.32-4.22(m,2H),3.78-3.60(m,4H),3.12(m,1H),2.99(m,2H), 2.80-2.71(m,2H), 2.32(S,2H),1.99(m,2H), 1.21(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.
Example 8 Synthesis of general formula 10
Adding 60g (0.165mol) of the compound of the general formula 9, 350g of tertiary butanol, 31.5 g (0.3mol) of sodium carbonate and 1.12 equivalent of 58.1g (0.185mol) of 2- [2- (2,2, 2-trifluoroethoxy) phenoxy ] ethyl methanesulfonate (compound 12) into a reaction flask, heating to the temperature of 90-100 ℃, reacting for 10-11 hours, removing the tertiary butanol under reduced pressure after the reaction is finished, adding 200g of water, extracting with 100g of toluene for three times, removing the solvent under reduced pressure, adding 200g of ethyl acetate into the residue, recrystallizing to obtain 64.3g of the compound of the general formula 10, wherein Y is 67%; HPLC purity 98.5%, ee 99.1%.
1H NMR(500MHz,CDCl3): δ 8.09-8.06(m,2H),7.68-7.56(m,3H), 7.42-7.25(m,2H),6.95-6.87 (m,4H),4.46-4.42(m,3H),4.32-4.22(m,2H),4.08-4.01(m, 2H),3.78-3.60(m,4H),3.12(m,1H),2.99-2.96(m,4H),2.80-2.71(m,2H),1.99(m, 2H), 1.19(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.
Example 9 synthesis of general formula 11:
adding 50g (0.086mol) of a compound with a general formula 10, 150g of ethanol and 6.5g of 10% Pd/C into a reaction bottle, adding into a pressure kettle, replacing with nitrogen for three times, replacing with hydrogen for two times, introducing hydrogen to 0.9-1.0Mpa, heating to 50-60 ℃, reacting for 3-4 hours, after the reaction is finished, recovering the catalyst by suction filtration, removing the solvent ethanol by decompression, and directly carrying out the next step on the obtained residue; adding 205g of DMSO and 1.2eq4.2g (0.1mol) of sodium hydroxide into the residue, dropwise adding 19.5g (0.17mol) of 30% hydrogen peroxide solution at 25-30 ℃, keeping the temperature at 25-30 ℃ to react for 3-4 hours after the addition is finished, adding 200g of water after the reaction is finished, extracting with 60g of DCM for three times each time, drying the organic phase by anhydrous sodium sulfate, carrying out suction filtration, removing DCM under reduced pressure, adding 60g of ethyl acetate into the residue, and recrystallizing to obtain 34g of the compound of the general formula 11, wherein Y is 80%; HPLC purity 99.5%, ee 99.3%.
1H NMR(500MHz,CDCl3): δ 7.90(s,2H),7.42-7.25(m,2H),6.95-6.87 (m,4H),4.51-4.41(m,4H),4.32-4.22(m,2H),4.08-4.01(m,2H),3.78-3.60(m, 4H),3.12(m,1H),2.99-2.96(m,4H),2.80-2.71(m,2H), 1.72(m,2H), 1.16(t, 3H). HPLC: XDB-C184.6 x 250, acetonitrile/water 1: 1,230 nm, 45 min. ee value: chiralpak IA-3(4.6X 250mm,3m), n-hexane, ethanol, diethylamine 60:40:0.3, 230nm, 30 min.

Claims (10)

1. A method for synthesizing silodosin is characterized by comprising the following steps:
(1) sequentially carrying out amino protection, bromination and deprotection reactions on indoline to obtain 5-bromoindoline 2;
Figure FDA0003000073310000011
(2) SN of 5-bromoindoline 2 and 2- (3-chloropropoxy) tetrahydro-2H-pyran2Reacting to obtain 5-bromo-1- [ 2-tetrahydropyran]Ethyl } -2H indole 3;
Figure FDA0003000073310000012
(3) performing substitution reaction on D-alanine and benzyl chloroformate to obtain an intermediate, performing Mannich reaction on the intermediate and formaldehyde to form a ring to obtain a cyclic ester compound;
Figure FDA0003000073310000013
(4) reacting the cyclic ester compound obtained in the step (3) with a Grignard reagent, reacting the obtained intermediate with the 5-bromo-1- [ 2-tetrahydropyran ] ethyl } -2H indole 3 obtained in the step (2) to obtain a compound 7, and sequentially carrying out reduction, benzoyl substitution and bromination on the compound 7 to obtain a compound 8;
Figure FDA0003000073310000014
(5) carrying out substitution reaction on the compound 8 and cuprous cyanide, and then removing a protecting group-CbZ to obtain a compound 9;
Figure FDA0003000073310000021
(6) compound 9 and 2- [2- (2,2, 2-trifluoroethoxy) phenoxy]Ethyl methanesulfonate 12 to SN2Substitution reaction to obtain a compound 10;
Figure FDA0003000073310000022
(7) compound 10 is deprotected first to remove protecting group BZThen oxidizing to obtain the silodosin;
Figure FDA0003000073310000023
2. the method for synthesizing silodosin according to claim 1, wherein in step (1), acetyl chloride is used as a protecting reagent for amino protection;
the brominating reagent is bromine, and the brominating is carried out in acetic acid;
the deprotection reaction is carried out in a mixed solvent of ethanol and water under the action of HCl.
3. According toThe method for synthesizing silodosin of claim 1, wherein in step (2), the SN is2The reaction is carried out in DMF under the action of inorganic base and potassium iodide.
4. The method for synthesizing silodosin according to claim 1, wherein in step (3), the substitution reaction is performed in water under the action of sodium hydroxide;
the Mannich reaction is carried out in toluene under the catalysis of p-toluenesulfonic acid.
5. The method for synthesizing silodosin according to claim 1, wherein in step (4), the Grignard reagent is i-PrMgCl.
6. The method for synthesizing silodosin according to claim 1, wherein in step (4), the reduction is performed under the action of triethylsilane and TFA.
7. The method for synthesizing silodosin according to claim 1, wherein in step (5), the substitution reaction is performed in DMF under the action of sodium iodide.
8. The method for synthesizing silodosin according to claim 1, wherein in step (5), the deprotection is performed under catalytic hydrogenation conditions, and the catalyst used in the catalytic hydrogenation is Pd/C.
9. The method for synthesizing silodosin according to claim 1, wherein in step (6), the SN is2The substitution reaction is carried out in a tert-butyl alcohol solvent at a temperature of 80-90 ℃.
10. The method for synthesizing silodosin according to claim 1, wherein in the step (7), the oxidant used for oxidation is hydrogen peroxide.
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